Nuove possibilità terapeutiche di seconda linea

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS Meldola

Ugo De Giorgi

Nuove possibilità terapeutiche di seconda linea

ECCO-ESMO 2015

FirstAuthor RCC

PresentationType

ChoueiriCabozantinib versus everolimus in patients with advanced renal cell carcinoma: Results of the randomized phase 3 METEOR trial

PresidentialOral

SharmaInterim Results From CheckMate 025, a Randomized,Open-Label, Phase 3 Study of Nivolumab vs Everolimusin Advanced or Metastatic Renal Cell Carcinoma

Presidential Oral

European Cancer Congress (ECC) 2015Annual Meeting Presentations

Abstract 4LBA

Cabozantinib versus everolimus in patients with advanced

renal cell carcinoma: results of a randomized phase 3 trial

(METEOR)

T. Choueiri, B. Escudier, T. Powles, P. Mainwaring, B. Rini, F. Donskov, H. Hammers, T. Hutson, B. Roth, K. Peltola, J-L. Lee, D. Heng, M. Schmidinger, A. Borgman-Hagey,

C. Hessel, C. Scheffold, G. Schwab, N. Tannir, R. Motzerfor the METEOR investigators

Presented at the European Cancer Congress, Vienna, 26 September 2015

Cabozantinib

• Cabozantinib is an oral small molecule inhibitor of tyrosine kinases including MET,

VEGF receptors, and AXL1

• A single arm trial of cabozantinib demonstrated clinical activity in heavily pretreated

RCC patients2

• The international, open-label phase 3 METEOR study evaluated the efficacy and

safety of cabozantinib compared to everolimus in VEGFR TKI pretreated RCC

patients

1 Yakes FM et al., Mol Cancer Ther, 20112 Choueiri TK et al., Ann Oncol, 2014


Study Design

Stratification:

• MSKCC1 risk groups: favorable, intermediate, poor

• Number prior VEGFR-TKIs: 1, 2 or more

Advanced RCC (N=650)• Clear cell histology

• Measurable disease

• Progression on prior VEGFR TKI within 6 months of

enrollment

• No limit to the number of prior therapies

• Antibodies targeting PD-1/PD-L1 allowed

• Brain metastases allowed if treated

Cabozantinib 60 mg qd orally

Everolimus 10 mg qd orally

Randomization 1:1No cross-over allowed

1 Motzer R. et al., J Clin Oncol, 2004

Tumor assessment by

RECIST 1.1 every 8 weeks

Treatment until loss of

clinical benefit or

intolerable toxicity


Statistical Design

• Primary endpoint: progression-free survival (PFS)– Assessed by independent radiology review committee (IRC)

– 259 events to achieve 90% power

– Among first 375 enrolled patients

– Hypothesized 50% increase in PFS (hazard ratio = 0.667)

• Secondary endpoints:– Overall survival (OS)

• 408 events among 650 planned patients

• Interim analysis at the time of primary PFS analysis

– Objective response rate (ORR) by IRC

Advanced RCC

OS

Population

N=650

PFS Population

N=First 375 RandomizedRandomization

1:1


Baseline Characteristics

Characteristic* Cabozantinib (N=330) Everolimus (N=328)

Median age, years (range) 63 (32‒86) 62 (31‒84)

Male, % 77 73

Enrollment Region, %

Europe / North America 51 / 36 47 / 37

Asia-Pacific & Latin America 14 16

ECOG Performance Status, %

0 68 66

1 32 34

MSKCC risk group1, %

Favorable 45 46

Intermediate 42 41

Poor 12 13

Metastatic sites per IRC, %

Lung 58 61

Liver 25 30

Bone 23 19

* Characteristics were consistent with the PFS population1 Motzer R. et al., J Clin Oncol, 2004


Progression-Free Survival Independent Central Radiology Review

8

M o n th s

Pro

gre

ss

ion

-fre

e S

urv

iva

l (%

)

0 3 6 9 1 2 1 5 1 8

0

2 0

4 0

6 0

8 0

1 0 0

No. at Risk Cabozantinib 187 152 92 68 20 6 2

Everolimus 188 99 46 29 10 2 0

Median PFS No. of

Events

mo (95% CI)

Cabozantinib (N=187) 7.4 (5.6-9.1) 121

Everolimus (N=188) 3.8 (3.7-5.4) 126

Hazard ratio, 0.58 (95% CI 0.45-0.75, P<0.001)


Progression-free Survival in Subgroups Independent

Radiology Review Committee

Subgroup Cabozantinib Everolimus Hazard Ratio (95% CI) no. of patients (events)

All patients 187 (121) 188 (126) 0.58 (0.45 - 0.75)

Prior VEGFR TKIs

One 137 (87) 136 (95) 0.56 (0.42 - 0.75)

Two or more 50 (34) 52 (31) 0.67 (0.41 - 1.10)

MSKCC risk group

Favorable 80 (51) 83 (56) 0.54 (0.37 - 0.79)

Intermediate 80 (49) 75 (47) 0.56 (0.37 - 0.84)

Poor 27 (21) 30 (23) 0.84 (0.46 - 1.53)

0 .2 5 0 .5 1 2 4

E v e ro lim u s B e tte rC a b o z a n tin ib B e tte r


Tumor Response – PFS PopulationIndependent Radiology Review Committee

Cabozantinib Everolimus

(N=187) (N=188)

Objective response rate, % 21 5

95% CI 16‒28 2‒9

P value < 0.001*

Best overall response, %

Complete response 0 0

Partial response 21 5

Stable disease 62 62

Progressive disease 14 27

Not evaluable or missing 3 6

* Cochran-Mantel-Haenszel test

The ORR was consistent in patients who received sunitinib as only prior VEGFR TKI


Tumor Response – PFS PopulationIndependent Radiology Review Committee

Cabozantinib Everolimus

(N=187) (N=188)

Objective response rate, % 21 5

95% CI 16‒28 2‒9

P value < 0.001*


Complete response 0 0

Partial response 21 5

Stable disease 62 62

Progressive disease 14 27

Not evaluable or missing 3 6

* Cochran-Mantel-Haenszel test

The ORR was consistent in patients who received sunitinib as only prior VEGFR TKI


M o n th s

Ov

era

ll S

urv

iva

l (%

)

0 3 6 9 1 2 1 5 1 8 2 1 2 4

0

2 0

4 0

6 0

8 0

1 0 0

C a b o z a n tin ib

E v e ro lim u s

No. at Risk Cabozantinib 330 317 294 189 101 32 6 1 0

Everolimus 328 306 260 156 88 24 5 1 0

Hazard ratio, 0.67 (95% CI 0.51-0.89, P=0.005)

Kaplan-Meier Estimates of Overall Survival Interim Analysis (49% Information Fraction)

The interim boundary to reach significance (P=0.0019) was not reached

Survival follow up is continuing to the planned final analysis

(Medians cannot yet be estimated due to frequent early censoring)


Exposure and Dose ReductionsSafety Population

Cabozantinib

(N=331)

Everolimus

(N=322)

Median duration of exposure – months (range)7.6

(0.3‒20.5)

4.4

(0.21‒18.9)

Median average daily dose 44 mg 9 mg

Any dose reduction 60% 25%

Discontinued due to adverse event 9% 10%

Dose reductions were used to adjust to the individual patient’s tolerability


All-causality Adverse Events

Cabozantinib (N=331) Everolimus (N=322)

Preferred Term, % All Grades Grade 3/4 All Grades Grade 3/4

Any adverse event* 100 68 >99 58

Diarrhea 74 11 27 2

Fatigue 56 9 46 7

Nausea 50 4 28 <1

Decreased appetite 46 2 34 <1

PPE syndrome 42 8 6 <1

Hypertension 37 15 7 3

Vomiting 32 2 14 <1

Weight decreased 31 2 12 0

Constipation 25 <1 19 <1

Anemia 17 5 38 16

Cough 18 <1 33 <1

Dyspnoea 19 3 28 4

Rash 15 <1 28 <1

Events of interest

Hyperglycaemia 5 <1 19 5

Pneumonitis 0 0 10 2

GI Perforation <1 <1 <1 <1

Fistula <1 <1 0 0

* Events reported in at least 25% of patients in either study group; PPE, palmar-plantar erythrodysesthesiaPresented at the European Cancer Congress, Vienna, 26 September 2015





Diarrhea 74 11 27 2

Fatigue 56 9 46 7

Nausea 50 4 28 <1




Vomiting 32 2 14 <1



Anemia 17 5 38 16

Cough 18 <1 33 <1

Dyspnoea 19 3 28 4

Rash 15 <1 28 <1

Events of interest




Fistula <1 <1 0 0






Diarrhea 74 11 27 2

Fatigue 56 9 46 7

Nausea 50 4 28 <1




Vomiting 32 2 14 <1



Anemia 17 5 38 16

Cough 18 <1 33 <1

Dyspnoea 19 3 28 4

Rash 15 <1 28 <1

Events of interest




Fistula <1 <1 0 0


METEOR Study Conclusions

• Cabozantinib significantly improves PFS compared to everolimus in RCC

patients after prior VEGFR TKI therapy

• Cabozantinib improved the objective response rate

• Overall survival results at the interim analysis show a strong trend favoring

cabozantinib

• Cabozantinib's safety profile is acceptable and tolerability is similar to other TKIs

in this population

• Cabozantinib represents a potential new treatment option for second or later line

therapy for RCC



ECCO-ESMO 2015ECCO-ESMO 2015

CheckMate 025: A Randomized, Open-Label,Phase III Study of Nivolumab

Versus Everolimus in AdvancedRenal Cell Carcinoma

Padmanee Sharma, Bernard Escudier, David F. McDermott, Saby George,Hans J. Hammers, Sandhya Srinivas, Scott S. Tykodi, Jeffrey A. Sosman, Giuseppe Procopio, Elizabeth R. Plimack, Daniel

Castellano, Howard Gurney, Frede Donskov, Petri Bono,John Wagstaff, Thomas C. Gauler, Takeshi Ueda, Li-An Xu, Ian M. Waxman,

Robert J. Motzer, on behalf of the CheckMate 025 investigators

ESMO (2015)

3LBA

21

CheckMate 025: Phase III Trial of Nivolumab versus Everolimus in 2L+ Advanced/Metastatic RCC

* Treatment beyond progression (RECIST 1.1) was allowed if investigator-assessed clinical benefit was achieved and treatment was well tolerated.

CNS, central nervous system; mTOR, mammalian target of rapamycin; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival; PS, performance status; qd, daily; q2w, every 2 weeks; R, randomized; RCC, renal cell carcinoma.Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813.

Nivolumab

3 mg/kg q2w Until progression*, unacceptable toxicity,

withdrawal of consent, or end of trial

Key Inclusion Criteria

• Advanced/metastatic clear cell RCC

• No more than 3 total prior regimens in advanced/metastatic setting

• 1 or 2 prior anti-angiogenic therapy regimens in advanced/metastatic setting

• No prior therapy with mTOR inhibitor

• Karnofsky PS ≥70%

• No CNS metastases

R

1:1

Everolimus

10 mg qd

Primary Outcome Measure: OSSecondary Outcome Measures: PFS, ORR, duration of objective response, duration of OS by PD-L1 status, safety, disease-related symptom progression rate

N=821

Checkmate 025: ORR1-3

* The proportion of patients achieving an overall response of complete response or partial response per RECIST version 1.1.† For patients without progression or death, duration of response was defined as the time from first response (CR/PR) date to the

date of censoring.CI, confidence interval; NE, not estimable; RECIST, response criteria in solid tumors.1. Motzer RJ et al. N Engl J Med. 2015;373(19): supplementary appendix. 2. Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813. 3. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2016.

Nivolumabn=410

Everolimusn=411

Confirmed Investigator Confirmed Investigator

Objective response rate, % (95% CI)* 21.5 25 3.9 5


Complete response 0.7 1 0.5 1

Partial response 20.7 24 3.4 5

Stable disease 35.9 34 54.5 55

Progressive disease 33.2 35 25.5 28

Not evaluated/unable to determine 9.5 6 16.1 12

Median duration of response, months (range)† 23.0 (12.0–NE) 12.0 (0–27.6) 13.7 (8.3–21.9) 12.0 (0–22.2)

CheckMate 025: DOR

Adapted from Motzer et al, 2015.

Based on data cut-off of June 2015. DOR, duration of response.Motzer et al. N Engl J Med. 2015;373(19):1803-1813.

Ongoing responseFirst responseOff treatment

NivolumabEverolimus

On treatment

0 16 32 6448 80Time (Weeks)

96 112 128

Resp

on

ders

CheckMate 025: PFS and OS

• In a post-hoc analysis of patients who had not progressed or died at 6 months, median PFS was 15.6 months for nivolumab vs 11.7 months for everolimus (HR [95% CI]: 0.64 [0.47–0.88])

Number of patients at risk

Nivolumab 410 230 145 116 81 66 48 29 11 4 0

Everolimus 411 227 129 97 61 47 25 16 3 0 0

0 3 6 129 15

Months

18 21 24 27 30

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

gre

ss

ion

-fre

e s

urv

iva

l (p

rob

ab

ilit

y)

Median PFS, months (95% CI)

Nivolumab 4.6 (3.7–5.4)

Everolimus 4.4 (3.7–5.5)

HR 0.88, 95% CI 0.75–1.03, P=0.11

Based on data cut-off of June 2015. CI, confidence interval; OS, overall survival; PFS, progression-free survival.Motzer et al. N Engl J Med. 2015;373(19):1803-1813.



Nivolumab 410 389 359 337 305 275 213 139 73 29 0

Everolimus 411 366 324 287 265 241 187 115 61 20 0

0 3 6 129 15

Months

18 21 24 27 33

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

30

Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

Median OS, months (95% CI)

Nivolumab 25.0 (21.7–NE)

Everolimus 19.6 (17.6–23.1)

HR 0.73, 95% CI 0.57–0.93, P=0.002

3

2


Nivolumab 18.5 (10.2–NE)

Everolimus 13.8 (7.0–16.4)

HR 0.72, 95% CI 0.47–1.09

Checkmate 025: OS in Patients with Bone Metastases*

* Analyses based on case report form data.CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival. Motzer RJ et al. Oral presentation at ASCO GU 2016. 498.

0 3 6 129 15

Months

18 21 24 27 30 33


Nivolumab 76 58 46 32 9 1

Everolimus 70 49 35 20 3 0

0.0

0.1

0.8

0.9

0.2

0.3

0.4

0.5

0.6

0.7

1.0


Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

Checkmate 025: treatment beyond progression—best reduction in target lesions with Nivolumab

• Approximately 50% of patients who received treatment despite progression had a reduction in tumor burden post-progression

• 14% had a ≥30% reduction in tumor burden post-progression

Patients

*

* * *

** *

** *

*

****

50

25

0

-25

-50

-75

-100

Be

st

Re

du

cti

on

fro

m F

irs

t P

rog

ress

ion

in T

arg

et

Les

ion

(%

)

* **

**

*

* ** * ****

□ □ □ □

Asterisks represent responders before first progression. Square symbols represent % change truncated to 100%.nivo, nivolumab; q2w, every 2 weeks.Escudier B et al. Poster presentation at ASCO 2016. 4509.

Checkmate 025: treatment beyond progression—Overall Survival with Nivolumab

CI, confidence interval; HR, hazard ratio; NE, not estimable; NTBP, not TBP; OS, overall survival; TBP, treated beyond progression.Escudier B et al. Poster presentation at ASCO 2016. 4509.


TBPNTBP

153 153 146 142 132 123 96 65 30 17 2 0145 131 113 101 84 69 54 29 16 3 0 0

Months

Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

0.0

0 3 6 9 12 15 18 21 24 27 30 33

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.0

0.9


Treated beyond progression 28.1 (23.2–NE)

Not treated beyond progression 15.0 (12.1–18.2)

HR 0.41, 95% CI 0.29–0.57

Adapted from Escudier et al, 20156.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

Pro

gre

ssio

n-F

ree S

urv

ival

(Pro

ba

bil

ity)

0 3 6 9 12

Progression-free survival

No. at RiskAll treated patients

aSimilar results were seen using the 5% PD-L1 tumor expression cutoff

265 110 48 17 0

Median PFS, Months (95% CI)a

All treated 2.00 (1.87–2.63)

All treated

patients

PD-L1 <1%

PD-L1 <1% 1.87 (1.77–2.04)

143 49 21 9 0PD-L1 <1%

PD-L1 ≥1% 3.55 (1.94–3.71)

122 61 27 8 0PD-L1 ≥1%

PD-L1 ≥1%

Overall survival

All treated patients

No. at RiskAll treated patients

PD-L1 <1%

PD-L1 ≥1%

PD-L1 ≥1%

Median OS, Months (95% CI)a

All treated 8.74 (6.05–NR)

PD-L1 <1% 5.95 (4.30–8.08)

PD-L1 ≥1% 11.30 (8.74–NR)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Overa

ll S

urv

ival

(Pro

ba

bil

ity)

Months

PD-L1 <1%

aSimilar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached

265 198 148 63 5 0143 101 69 26 2 0

122 97 79 37 3 0

CheckMate 025: Treatment-Related AEsNivolumab

N=406Everolimus

N=397Any grade Grade 3 Grade 4* Any grade Grade 3 Grade 4†

Treatment-related AEs, % 79 18 1 88 33 4

Fatigue 33 2 0 34 3 0

Nausea 14 <1 0 17 1 0

Pruritus 14 0 0 10 0 0

Diarrhea 12 1 0 21 1 0

Decreased appetite 12 <1 0 21 1 0

Rash 10 <1 0 20 1 0

Cough 9 0 0 19 0 0

Anemia 8 2 0 24 8 <1

Dyspnea 7 1 0 13 <1 0

Edema peripheral 4 0 0 14 <1 0

Pneumonitis 4 1 <1 15 3 0

Mucosal inflammation 3 0 0 19 3 0

Dysgeusia 3 0 0 13 0 0

Hyperglycemia 2 1 <1 12 3 <1

Stomatitis 2 0 0 29 4 0

Hypertriglyceridemia 1 0 0 16 4 1

Epistaxis 1 0 0 10 0 0

Based on data cut-off of June 2015. * Grade 4 AEs not listed in table: increased blood creatinine (1), acute kidney injury (1), anaphylactic reaction (1). † Grade 4 AEs not listed in table: increased blood triglycerides (2), acute kidney injury (1), sepsis (1), chronic obstructive pulmonary disorder (1), increased blood cholesterol (1), neutropenia (1), pneumonia (1). AE, adverse event. Sharma P et al. Oral presentation at ESMO 2015. 3LBA.

CheckMate 025: HRQoLMean change from baseline in HRQoL scores by FKSI-DRS: descriptive analysis

a Significant improvement (P<0.05) from baseline in FKSI-DRS for nivolumab.b Significant improvement (P<0.05) in FKSI-DRS mean change from baseline scores between nivolumab and everolimus arms.c Significant deterioration (P<0.05) from baseline in FKSI-DRS for everolimus.Note: only time points where data were available for ≥5 patients are plotted.FKSI-DRS, Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms.Cella DF et al. Oral presentation at ASCO 2016. 4549.

-6

-4

-2

0

2

4

6

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

361 334 302 267 236 208 186 164 159 144 132 119 112 97 90 89 81 72 63 59 53 44 43 31 30 26 20Nivolumab

343 316 270 219 191 157 143 122 102 97 87 74 73 63 58 49 44 35 30 28 24 21 15 12 12 9 9Everolimus


Treatment visit (week)

Mea

n c

han

ge f

rom

bas

elin

e

a

b

c c

Nivolumab

Everolimus

Be

tte

rW

ors

e

Adapted from Cella et al, 2016.

ASCO 2016

Long-term Overall Survival (OS) With Nivolumab in Previously Treated Patients

With Advanced Renal Cell Carcinoma (aRCC) From Phase I and Phase II Studies

David F. McDermott,1 Robert J. Motzer,2 Michael B. Atkins,3 Elizabeth R. Plimack,4

Mario Sznol,5 Saby George,6 Charles G. Drake,7 Brian Rini,8 Toni K. Choueiri,9 Timothy Kuzel,10

Jeffrey A. Sosman,11 David C. Smith,12 Ulka Vaishampayan,13 John D. Powderly,14

Suzanne L. Topalian,7 Huanyu Zhao,15 Ian M. Waxman,15 Hans J. Hammers7

1Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 4Fox Chase Cancer Center, Philadelphia, PA, USA; 5Yale

University School of Medicine and Smilow Cancer Center, Yale–New Haven Hospital, New Haven, CT, USA; 6Roswell Park Cancer Institute, Buffalo, NY, USA; 7Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 8Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 9Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, USA; 10Northwestern University

Feinberg School of Medicine, Chicago, IL, USA; 11Vanderbilt University Medical Center, Nashville, TN, USA; 12University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 13Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 14Carolina

BioOncology Institute, Huntersville, NC, USA; 15Bristol-Myers Squibb, Princeton, NJ, USA

4507

ASCO 2016

Designs of Phase I and II Studies

Phase I Study (NCT00730639)

Phase II Study (NCT01354431)

• PD after 1–5 systemic therapies

• ECOG PS ≤2

Key criteria

1 or 10 mg/kg nivolumabIV Q2W (RCC)

8-week treatment cycle

• Treat until confirmed progressiona or unacceptable toxicity

• Treatment duration:

– 96 weeks if clinically stable

Endpoints

• Primary: Safety and tolerability

• Key secondary: ORR

Arm 10.3 mg/kg nivolumab IV Q3W

Arm 22 mg/kg nivolumab IV Q3W

Arm 310 mg/kg nivolumab IV Q3W

• 1–3 prior therapies

• ≥1 prior anti-angiogenic agent

• PD after last therapy and ≤6 months prior to enrollment

• KPS ≥70%

• Treat until confirmed progressiona or unacceptable toxicity

• Treatment duration:

– Continuous if clinically stable

Endpoints

• Primary: Dose response by PFS

• Key secondary: Response rate, OS, toxicities R

an

do

miz

e 1

:1:1

b

Key criteria

aTreatment beyond progression was permitted if nivolumab was tolerated and clinical benefit was noted.bRandomization stratified by MSKCC risk group and number of prior therapies in metastatic setting.

ASCO 2016

Baseline Characteristics in Phase I and II Studies

aAll treated patients; bAll randomized patients; cOne patient had a deviation to KPS <70%.

1. McDermott DF, et al. J Clin Oncol 2015;33:2013–20. 2. Motzer RJ, et al. J Clin Oncol 2015;33:1430–37.

Phase I1

N = 34a

Phase II2

N = 168b

Median age, years (range) 58 (35, 74) 61 (37, 81)

Sex, %

Male

Female

76

24

72

28

MSKCC risk group, %

Favorable

Intermediate

Poor

–

–

–

33

42

25

KPS, %

90 or 100

70 or 80c

–

–

54

46

ECOG performance status, %

0

1

50

50

–

–

No. of prior systemic therapies, %

1

>1

29

71

30

70

ASCO 2016

Overall Survival in Phase I and II Studies

NE, not estimable.

34 28 24 18 14 13 12 12 11 8 6 6 2 1 0

167 142 113 93 80 65 58 51 47 2 0 0 0 0 0

StudyMedian OS, months

(95% CI)

Phase I 22.4 (12.5–NE)

Phase II 23.4 (17.7–26.9)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

No. of patients at risk

Phase I

Phase II

Overa

ll S

urv

ival

(Pro

bab

ilit

y)

Months

38%

29%

34%

• In phase I and II studies, minimum follow-up was 50.5 months and 49.2 months, respectively

ASCO 2016

Survival by MSKCC Risk Group in Phase II Study

1. Motzer RJ, et al. J Clin Oncol 2004;22:454–63.

56 52 47 40 36 28 25 22 18 1

70 59 45 38 33 28 25 23 23 1

42 32 22 15 11 9 8 6 6 0

0 6 12 18 24 30 36 42 48 54

MonthsNo. of patients at risk

Favorable

Intermediate

Poor

MSKCC risk group1


Favorable (0) 35.5 (25.5–43.0)

Intermediate (1) 22.1 (17.7–26.9)

Poor (2–3) 12.5 (9.3–13.7)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0O

vera

ll S

urv

ival

(Pro

bab

ilit

y)

ASCO 2016

Survival by KPS in Phase II Study

KPSMedian OS, months

(80% CI)

90 or 100 27.2 (25.2–39.1)

70 or 80 14.6 (11.7–18.6)

77 57 43 33 28 22 17 15 15 2

0 6 12 18 24 30 36 42 48 54

MonthsNo. of patients at risk

KPS 90 or 100

KPS 70 or 80

90 85 70 60 52 43 41 36 32 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0O

vera

ll S

urv

ival

(Pro

bab

ilit

y)

ASCO 2016

Survival by Response in Phase II Study

No. of patients at riska

CR/PR

SD

PD

4 10 16 22 28 34 40 46 52 58

Months

23 22 21 19 19 18 16 15 2 0

80 69 58 49 38 35 29 26 9 0

51 32 20 17 11 9 9 9 1 0

ResponseMedian OS, months

(95% CI)

CR/PR NR (34.3–NE)

SD 22.9 (18.7–31.8)

PD 9.0 (5.9–14.2)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0O

vera

ll S

urv

ival

(Pro

bab

ilit

y)

aAll treated patients evaluable for best overall response by 4 months.

ASCO 2016

Emergence of Select Treatment-related AEs (Any Grade) Over Time in Phase II Study

0

5

10

15

20

25

30

35

40

45

Overall ≤6 >6–≤12 >12–≤18 >18–≤24 >24–≤30 >30–≤36 >36

Months

Even

ts/p

ati

en

ts a

t ri

sk (

%)

167 167 88 62 44 36 25 21No. of patients at risk

• Select treatment-related AEs included endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin

ASCO 2016


0

5

10

15

20

25

30

35

40

45

Overall ≤6 >6–≤12 >12–≤18 >18–≤24 >24–≤30 >30–≤36 >36

Months

Even

ts/p

ati

en

ts a

t ri

sk (

%)



ASCO 2016

0

5

10

15

20

25

30

35

40

45

Overall ≤6 >6–≤12 >12–≤18 >18–≤24 >24–≤30 >30–≤36 >36

Months


Even

ts/p

ati

en

ts a

t ri

sk (

%)



ASCO 2016

Characteristics of Patients Alive at ≥4 Years in Phase II Study

• 15/48 patients alive at 4 years did not require subsequent therapy

N = 48

MSKCC risk group, %

Favorable

Intermediate

Poor

40

44

17

KPS, %

90 or 100

70 or 80

69

31


CR

PR

SD

PD

2

46

33

19

ASCO 2016

Long-term OS with Nivolumab

Conclusions

• This is the longest follow-up reported with PD-1/PD-L1 agent in mRCC

• After treatment with nivolumab in a second-line or later setting, these data show:

– Approximately one-third of patients are alive at 4 years (phase I and II) and 5 years (phase I)

– Long-term survival is achievable regardless of risk group, performance status, or best overall response (phase II)

– Safety profile is consistent with prior reports, and most select treatment-related AEs occur within 6 months

* MCBS-FT.ESMO, European Society for Medical Oncology; GR, recommendation grade; IFN, interferon; IL-2, interleukin-2; LE, level of evidence; MCBS, ESMO Magnitude of Clinical Benefit Scale v1.0; MCBS-FT, MCBS-field testing; RCC, renal cell carcinoma, TKI, tyrosine kinase inhibitor.1. Escudier B et al. Ann Oncol. 2016;27(supplement 5):v58-v68. 2, Kiesewetter B et al. ESMO Open. 2016;1:e000066. doi:10.1136/ esmoopen-2016-000066.

ESMO Guidelines: Treatment Algorithm for Advanced RCC1,2

Good or intermediate riskLE, GR, MCBS Poor risk

LE, GR, MCBS

First Line

StandardSuntinib

Bevacizumab + IFNPazopanib

I, A, 4I, A, 3*

I, ATemsirolimus II, A, 4*

OptionHigh dose IL-2

SorafenibBevacizumab + low dose IFN

III, CII, BIII, B

SunitnibSorafenibPazopanib

II, BIII, BIII, B

Post cytokinesLE, GR. MCBS Post TKIs

LE. GR, MCBS

Second Line

StandardAxitinib

SorafenibPazopanib

II, A, 3I, A, 3II, A, 3

NivolumabCabozantinib

I, A, 5*I, A, 3*

Option Suntinib III, AAxitinib

EverolimusSorafenib

II, B, 3II, B, 3III, B, 3

Post two TKIs LE, GR Post TKI & mTOR LE, GRPost TKI & nivolumab LE, GR

Post TKI & cabozantinib LE, GR

Third LineStandard

NivolumabCabozantinib

II, AII, A

SorafenibNivolumab

Cabozantinib

I, BV, AV, A

Cabozantinib V, A Nivolumab V, A

Option Everolimus II, BOther TKI

RechallengeIV, BIV, B

AxitinibEverolimus

IV, CIV, C

EverolimusAxitinib

V, BV, B

45

RingraziamentiSSD Oncologia Genito-urinariaUgo De GiorgiLuca BurgioCecilia MennaVincenza ConteducaCristian LolliGiuseppe SchepisiOrnella Carminati (sede Cesena) Lorena Rossi (specializzanda)

Laboratorio Bioscienze – T. GenitourinariValentina CasadioSamanta SalviGiorgia Gurioli

Biostatistica e data manager – T. GenitourinariSara TestoniValentina Gallà

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